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Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma
| Content Provider | Scilit |
|---|---|
| Author | Deken, Marcel A. Gadiot, Jules Jordanova, Ekaterina S. Lacroix, Ruben Gool, Melissa Van Kroon, Paula Pineda, Cristina Foppen, Marnix H. Geukes Scolyer, Richard Song, Ji-Ying Verbrugge, Inge Hoeller, Christoph Dummer, Reinhard Haanen, John B. A. G. Long, Georgina V. Blank, Christian U. |
| Copyright Year | 2016 |
| Description | Journal: OncoImmunology Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients. Preclinical data endorsing this hypothesis are accumulating. Inhibition of the PI3K-Akt-mTOR pathway may be a promising treatment option to overcome resistance to MAPK inhibition and for additional combination with immunotherapy. We therefore evaluated to which extent dual targeting of the MAPK and PI3K-Akt-mTOR pathways affects tumor immune infiltrates and whether it synergizes with PD-1 checkpoint blockade in a $BRAF^{V600E}/PTEN^{−/−}$-driven melanoma mouse model. Short-term dual BRAF + MEK inhibition enhanced tumor immune infiltration and improved tumor control when combined with PD-1 blockade in a $CD8^{+}$ T cell dependent manner. Additional PI3K inhibition did not impair tumor control or immune cell infiltration and functionality. Analysis of on-treatment samples from melanoma patients treated with BRAF or BRAF + MEK inhibitors indicates that inhibitor-mediated T cell infiltration occurred in all patients early after treatment initiation but was less frequent found in on-treatment biopsies beyond day 15. Our findings provide a rationale for clinical testing of short-term BRAF + MEK inhibition in combination with immune checkpoint blockade, currently implemented at our institutes. Additional PI3K inhibition could be an option for BRAF + MEK inhibitor resistant patients that receive targeted therapy in combination with immune checkpoint blockade. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215252/pdf |
| e-ISSN | 2162402X |
| DOI | 10.1080/2162402x.2016.1238557 |
| Journal | OncoImmunology |
| Issue Number | 12 |
| Volume Number | 5 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2016-12-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: OncoImmunology Research and Experimental Medicine Checkpoint Blockade Immunotherapy Targeted Therapy |
| Content Type | Text |
